Chimaerins, Novel Non-protein Kinase C Phorbol Ester Receptors, Associate with Tmp21-I (p23)

Wang, Hongbin; Kazanietz, Marcelo G.

doi:10.1074/jbc.m107150200

Cited by 61 publications

(96 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A cytosolic protein PKC has been shown to play an important role in platelet aggregation by pharmacological experiments using cell-permeable small compounds of inhibitors and stimulators such as phorbol esters (16,17). However, the results obtained from such experiments appear somewhat indirect because the specificity of inhibitors is not absolutely strict and important signaling molecules containing the phorbol ester-binding C1 domain other than PKC have been recently identified such as Ras-guanyl nucleotide-releasing protein (11,12) and chimerin (13,14). Munc13-1 present in the presynapse also contains the C1 domain (38), and it has very recently been demonstrated that the effect of phorbol ester in the neurotransmitter release is through Munc13-1 (39).…”

Section: Discussionmentioning

confidence: 88%

“…For example, Ras-guanyl nucleotide-releasing protein (11,12) contains the C1 domain at its C terminus and acts as a stimulator for small GTPase Ras involved in the regulation of cell growth. Chimerin (13,14) also contains a C1 domain and acts as a GTPase-activating protein of small GTPase Rac involved in the regulation of cytoskeletal reorganization. Thus, the effects of phorbol esters could be through multiple pathways.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Direct Demonstration of Involvement of Protein Kinase Cα in the Ca2+-induced Platelet Aggregation

Tabuchi¹,

Yoshioka²,

Higashi³

et al. 2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

Platelets play critical roles in hemostasis and thrombosis through their aggregation following activation of integrin ␣ IIb ␤ 3 . However, the molecular mechanism of the integrin activation inside platelets remains largely unknown. Pharmacological experiments have demonstrated that protein kinase C (PKC) plays an important role in platelet aggregation. Because PKC inhibitors can have multiple substrates and given that non-PKC-phorbol ester-binding signaling molecules have been demonstrated to play important roles, the precise involvement of PKC in cellular functions requires re-evaluation. Here, we have established an assay for analyzing the Ca 2؉ -induced aggregation of permeabilized platelets. The aggregation of platelets was inhibited by the addition of the arginine-glycine-aspartate-serine peptide, an integrin-binding peptide inhibitor of ␣ IIb ␤ 3 , suggesting that the aggregation was mediated by the integrin. The aggregation was also dependent on exogenous ATP and platelet cytosol, indicating the existence of essential cytosolic factors required for the aggregation. To examine the role of PKC in the aggregation assay, we immunodepleted PKC␣ and ␤ from the cytosol. The PKC-depleted cytosol lost the aggregation-supporting activity, which was recovered by the addition of purified PKC␣. Furthermore, the addition of purified PKC␣ in the absence of cytosol did not support the aggregation, whereas the cytosol containing less PKC supported it efficiently, suggesting that additional factors besides PKC would also be required. Thus, we directly demonstrated that PKC␣ is involved in the regulation of Ca 2؉ -induced platelet aggregation.Platelets play critical roles in hemostasis and thrombosis through aggregation following activation of integrin ␣ IIb ␤ 3 (1-3). Although ␣ IIb ␤ 3 of platelets in the resting stage does not bind fibrinogen or von Willebrand factors (vWF), 1 the activation of platelets results in conformation changes, which allow ␣ IIb ␤ 3 to bind these ligands (1-3). When fibrinogen or vWF binds to ␣ IIb ␤ 3 , the ligand-occupied integrin signals downstream to stabilize platelet aggregation through reorganization of the actin cytoskeletal network and the release of bioactive substances stored in the granules (1-3). Thus, the process of platelet activation and aggregation consists of a series of orchestrated responses (1-3). However, the molecular mechanisms that underlie this process remain unclear because it is difficult to use molecular biology and biochemistry in platelets that do not synthesize new proteins. To overcome this difficulty, semi-intact assays using permeabilized platelets have been established for the study of granule secretion (4 -8). Although some semi-intact aggregation assays have now been developed, it has been difficult to demonstrate a cytosol dependence in these experiments (8).Protein kinase C (PKC) family members are important signaling molecules regulating many cellular functions (9, 10). Among the family members, conventional PKCs (cPKC), which include PKC␣, ␤I, ␤II, and ␥...

show abstract

Section: Discussionmentioning

confidence: 88%

mentioning

confidence: 99%

Direct Demonstration of Involvement of Protein Kinase Cα in the Ca2+-induced Platelet Aggregation

Tabuchi¹,

Yoshioka²,

Higashi³

et al. 2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…2 Based on those results, we surmise that the localization of RasGRP1 in the endoplasmic reticulum is helped by the binding of the RasGRP1 ZF to a docking protein present in that subcellular compartment. A similar targeting mechanism has been proposed recently for chimerins (21), a group of phorbol ester receptors that act as GAPs for Rho/Rac GTPases (20). We are currently conducting yeast two-hybrid experiments to characterize the possible binding partners for the RasGRP1 ZF domain in the endoplasmic reticulum.…”

Section: Discussionmentioning

confidence: 99%

Exchange Factors of the RasGRP Family Mediate Ras Activation in the Golgi

Caloca¹,

Zugaza²,

Bustelo

2003

Journal of Biological Chemistry

136

115

View full text Add to dashboard Cite

“…37,38 DAG is a lipid second messenger generated directly by the action of phospholipase C isozymes or indirectly via the activation of phospholipase D and subsequent release of phosphatidic acid (PA), a phospholipid signaling molecule. These DAG receptors act as GTPase accelerating proteins, which enhance cellular G-protein signal transduction.…”

Section: Discussionmentioning

confidence: 99%

Antipsychotic drug treatment alters expression of mRNAs encoding lipid metabolism-related proteins

et al. 2003

View full text Add to dashboard Cite

Using an automated PCR-based genomics approach, TOtal Gene expression Analysis (TOGA s ), we have examined gene expression profiles of mouse striatum and frontal cortex in response to clozapine and haloperidol drug treatment. Of 17 315 mRNAs observed, TOGA s identified several groups of related molecules that were regulated by drug treatment. The expression of some genes encoding proteins involved in neurotransmission, signal transduction, oxidative stress, cell adhesion, apoptosis and proteolysis were altered in the brains of both clozapine-and haloperidol-treated mice as recognized by TOGA s . Most notable was the differential expression of those genes whose products are associated with lipid metabolism. These include apolipoprotein D (apoD), the mouse homolog of oxysterol-binding protein-like protein 8 (OSBPL8), a diacylglycerol receptor (n-chimerin), and lysophosphatidic acid (LPA) acyltransferase. Real-time PCR analysis confirmed increases in the RNA expression of apoD (1.6-2.2-fold) and OSBPL8 (1.7-2.6-fold), and decreases in the RNA expression of nchimerin (1.5-2.2-fold) and LPA acyltransferase (1.5-fold) in response to haloperidol and/or clozapine treatment. Additional molecules related to calcium homeostasis and signal transduction, as well as four sequences of previously unidentified mRNAs, were also confirmed by real-time PCR to be regulated by drug treatment. While antipsychotic drugs may affect several metabolic pathways, lipid metabolism/signaling pathways may be of particular importance in the mechanisms of antipsychotic drug action and in the pathophysiology of psychiatric disorders. Molecular Psychiatry (2003) 8, 983-993.

show abstract

Chimaerins, Novel Non-protein Kinase C Phorbol Ester Receptors, Associate with Tmp21-I (p23)

Cited by 61 publications

References 47 publications

Direct Demonstration of Involvement of Protein Kinase Cα in the Ca2+-induced Platelet Aggregation

Direct Demonstration of Involvement of Protein Kinase Cα in the Ca2+-induced Platelet Aggregation

Exchange Factors of the RasGRP Family Mediate Ras Activation in the Golgi

Antipsychotic drug treatment alters expression of mRNAs encoding lipid metabolism-related proteins

Contact Info

Product

Resources

About